The goal of the proposed research is to further develop fundamental aspects of copper coordination chemistry relevant to its essential role in the biochemical processing of dioxygen (O2) and nitrogen oxides (NOx). Many questions remain concerning copper(l)/O2 interactions, dynamics &energetics of O2-adduct formation, as well as questions concerning structure, associated spectroscopy, O-O bond cleavage (i.e., O2- activation) and substrate oxidation chemistries. These may also be relevant to situations of oxidative stress, e.g., in neurological disorders such as Alzheimer's disease. Copper-NOx investigations are relevant to the active site chemistry in nitrite and nitrous oxide (N2O) reductases, and to the possible role of copper ion in nitrogen monoxide ("NO) biochemistry, including mediation of O2 with -NO peroxynitrite (O=NOO~) chemistry and oxidative (and/or nitrative) stress. The research methods divide into sub-projects, directed along various themes or chemical systems. These include (1) study of O2 and carbon monoxide (CO, as O2-surrogate) kinetics and thermodynamics of binding to tetradentate ligand Cu(l)-chelates, (2) study of key ligand- Cu2+(O2-) (superoxide) solvent hydrogen bonding and photochemistry, (3) a major effort to unravel mechanistic details of ligand-Cu2+(O2-) substrate reactivity involving hydrogen-atom transfer chemistry, (4) study of new tetradentate ligand-Cu complexes including with thioether donors, of relevance to certain Cu- monooxygenases, emphasizing O2 &CO binding kinetics-thermodynamics and structural-spectroscopic comparisons to other systems, (5) transient absorption spectroscopic detection of previously unobserved primary Cu/O2 =1:1 adducts and elucidation of their kinetics-thermodynamics and spectroscopy, employing highly reactive tridentate ligand Cu complex systems, (6) investigation of copper ion complexation, structure, binding and chemical reactivity with histidine-histidine peptide moieties (novel binding motifs in copper biochemistry), emphasizing previously un-researched copper(l) coordination chemistry of HisHis and the known metal binding portion (residues 6-14) of the Alzheimer's disease associated amyloid ??peptide, (7) elaboration of Cu-sulfide chemistry, including generation and characterization of new cluster compounds relevant to the active site of nitrous oxide reductase, with additional emphasis placed on the complexes'ability to reductively activate N2O, and (8) investigation of ligand Cu+ reactions with NO and O2, leading to peroxynitrite-derived chemistry. The proposed studies contribute to a broader understanding of copper biochemistry, other metalloprotein (e.g., heme or non-heme iron) activation/reduction of O2 and NOx in biology and associated disease states. Potential long-term applications of this basic research include development of enzyme inhibitors and relevant disease therapeutic strategies.